DESCRIPTION (Applicant's Abstract): This application outlines a training program to be carried out under the mentorship of Dr. Stephen Desiderio in the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. The applicant's goals are to study the role of a transcription factor, BAP135, in normal neuronal function, as well as to evaluate this gene as a candidate for the neurocognitive phenotype of Williams Syndrome. The training program has been designed to gain expertise in the fields of molecular biology and transcriptional regulation. BAP135 is a recently described transcription factor which appears to define a new family that also includes WBSCR11. BAP135 mRNA is expressed in multiple tissues in mouse, but is most abundant in regions of the central nervous system. Expression of BAP135 is highest during the development of synaptic connections and remains high in areas of ongoing synaptic plasticity. The pattern of BAP135 expression is of further interest as the gene for BAP135 maps to the region of chromosome 7 commonly deleted in the genetic disorder, Williams Syndrome. This syndrome includes a characteristic neurocognitive defect which might be explained by deletion of a transcription factor such as BAP135. Studies are proposed to gain an understanding of how BAP135 functions as a transcriptional activator in neurons. As part of Specific Aim 1, the cellular and subcellular localization of BAP135 protein with development will be established. This will also address the patterns of expression of the four isoforms of BAP135 known to exist. Several aspects of the induction of BAP135 transcriptional activation will be addressed in Specific Aim 2. Both DNA binding of BAP135 and transactivation of reporter constructs in neurons will be evaluated and the effect of pathways involved in synaptic plasticity on these functions will be addressed. Specific Aim 3 focuses on the pathway downstream of BAP135 in neurons. Genes modulated by BAP135 activity will be investigated using DNA expression arrays. Finally, in Specific Aim 4, lymphoblast lines from patients with Williams Syndrome will be examined for deletions and mutations in the BAP135 locus. Mutations identified will be evaluated for effects on DNA binding and transactivation by BAP135 in neurons.